Generation of therapeutic microfoam

ABSTRACT

Improved therapeutic sclerosing microfoams and methods and devices for making them are provided that have advantage in producing a consistent profile injectable foam with minimal input by the physician yet using high volume percentages of blood dispersible gases, thus avoiding use of potentially hazardous amounts of nitrogen.

The present invention relates to the generation of microfoam comprisinga sclerosing material, particularly a sclerosing liquid, which issuitable for use in the treatment of various medical conditionsinvolving blood vessels, particularly varicose veins and other disordersinvolving venous malformation.

Sclerosis of varicose veins is based on the injection into the veins ofliquid sclerosant substances which, by inter alia causing a localisedinflammatory reaction, favour the elimination of these abnormal veins.When a sclerosing substance is injected in liquid form, it is mixed withthe blood contained in the vein and is diluted in an unknown proportion.The results are uncertain, owing to over- or under-dosage, and arelimited to short varicose segments. As the size of the varicose veins tobe injected decreases, this dilution is less and the results obtainedare more predictable.

Until recently, sclerosis was a technique selected in cases of small andmedium varicose veins, those with diameters equal to or greater than 7mm being treated by surgery. Sclerosis and surgery complemented oneanother but sclerosis treatment continued not to be applicable to largevaricose veins. In these large varicose veins, if a sclerosing substancewas injected, its concentration in the vein, its homogeneousdistribution in the blood, and the time for which it is in contact withthe internal walls of the vessel treated were not known.

In 1946, Orbach injected a few cubic centimetres of air into smallvaricose veins and confirmed a displacement of the blood inside thevessel which was occupied by the injected air. A sclerosing solutionintroduced immediately afterwards was more effective than if it had beeninjected into the blood. However, in thick varicose veins, when air isinjected the phenomenon described of the displacement of the blood bythe injected air does not occur but the air forms a bubble inside thevein which makes the method ineffective in these vessels.

The same author had the idea, a few years later, of injecting foamobtained by agitation of a container containing sodium tetradecylsulphate, which is an anionic sclerosing detergent with a good foamingcapability. The method was of little use owing to the large size of thebubbles formed and was dangerous owing to the side effects ofatmospheric nitrogen which is only slightly soluble in blood. Bothmethods had limited practical repercussion being used only in smallvaricose veins.

An injectable microfoam suitable for therapeutic uses has now beendeveloped and is described in EP 0656203 and U.S. Pat. No. 5,676,962(incorporated herein by reference). These patents describe a microfoamproduced with a sclerosing substance which, when injected into a vein,displaces blood and ensures that the sclerosing agent contacts theendothelium of the vessel in a known concentration and for acontrollable time, achieving sclerosis of the entire segment occupied.

The advantages of use of this foam are that it allows the concentrationof the sclerosing agent in the blood vessel to be known, since themicrofoam displaces the blood and is not diluted therein in to the sameextent as a simple liquid would be.

Furthermore it allows homogeneous distribution of the sclerosis productin the vein to be ensured and the time for which it is kept in contactwith the internal walls of the vein to be controlled. None of whichfactors is known precisely or is controllable with the use of sclerosingagents in simple liquid form.

The preparation of such a microfoam may be carried out with a solutionof any sclerosing substance, particularly polidocanol, alkali metaltetradecyl sulphate eg. sodium salt, hypertonic glucose or gluco-salinesolutions, chromic glycerol, ethanolamine oleate, sodium morrhuato oriodic solutions.

However, this known method requires production of microfoam by thephysician, pharmacist or an assistant immediately prior toadministration to the patient. Such procedure allows for variation ofagent depending upon the person preparing it, with content of gas,bubble size and stability all needing attention with respect to thecondition being treated. It also requires a high degree of care andknowledge that may be difficult to replicate under pressure, ie. whentime available to prepare the foam is short.

The method particularly described in the aforesaid patents uses a highspeed beating action with a brush to generate a foam of correctproperty. Other reported techniques in use do not produce such uniform,stable or injectable microfoam and notably include those where gas isbubbled, eg sparged into the sclerosant, eg. by leakage into asclerosant filled syringe from around the side of the syringe plunger.

Furthermore, a problem in using air as the gas for producing the foam isthe perception that large volumes of nitrogen should not unnecessarilybe introduced into patients, particularly where large vessels are beingfilled with foam and eliminated. Gas embolism with nitrogen remains apossibility.

The solubility of physiological gases in aqueous fluids, such as blood,varies considerably. Thus while nitrogen is almost twice as insoluble inwater as oxygen at STP, carbon dioxide is over fifty times as soluble inaqueous liquids as nitrogen and over twenty five times as soluble asoxygen.

TABLE 1 Solubility of Gases in water at STP Gas Mole Fraction Solubility10⁻⁵ Helium 0.7 Nitrogen 1.18 Oxygen 2.3 Xenon 7.9 Nitrous oxide 43.7Carbon dioxide 61.5

At the present time it is perceived that production of such microfoamwith gases incorporating high proportions of gas that is readilydispersed in blood, such as carbon dioxide, would be desirable for thepurposes of minimising the prospect of the treatment producing a gasembolism. However, it is also perceived by practitioners that this isdifficult task due to its high solubility in water.

It would also be desirable to provide a relatively stable microfoam ofuniform character that is readily producible by use of a relativelysimple and reliable mechanism, rather than one involving use of highspeed mixing or beating, the time of performance of which may affectfoam property.

It is particularly desirable that the microfoam so produced may bepassed through a needle of gauge suitable for injecting into bloodvessels without being significantly converted back to its separate gasand liquid components and/or changing characteristics such assignificantly increasing bubble sizes.

Such a needle may be of very small diameter, eg a 30 gauge needle (0.14mm interior diameter). More typically it will be larger eg. an 18 to 22gauge needle (interior diameter 0.838 to 0.394 mm), more preferably 19to 21 gauge (interior diameter. 0.686 mm).

The rate at which the foam is passed down the needle can be such thatany foam might be broken down, but it is desirable that a foam isproduced that does not break down under normal injection conditions, ie.at rates compatible with control of entry of foam into a vein. Forexample, it should withstand injection at rates of 0.1 to 0.5 ml/second,more preferably 0.3 to 1 ml/second for a 19 to 21 gauge needle.

It is still further desirable to provide a device that is of steriletype with regard to the foam it generates particularly with regard tomicro-organisms and pyrogens.

It is particularly desirable to provide a sealed device that operates toproduce foam of set property suitable for a given medical procedurewithout technical input from the physician who will perform theprocedure, or assistants thereof.

One form of device that could potentially provide these desiredproperties would be an aerosol dispenser of a type that produces foams.However, for the purposes of generating a microfoam to be injected intoa human or animal body, it is undesirable to have a propellant gas ofthe type usually employed in aerosol canisters, eg such as isopropane.This determines that the gas from which the foam is to be made mustitself be pressurised to allow production of foam.

Water soluble gases such as carbon dioxide have been found by theinventors to be incapable of producing a stable foam when generated bymerely being passed through a standard aerosol valve under pressure,such as might be expected to convert a detergent solution such as one ofpolidocanol or sodium tetradecylsulphate to a foam. They have determinedthat when this gas is used under pressure to propel a sclerosing agentsolution through a conventional aerosol valve the foam produced, whileinitially containing at least some microfoam structure, is notsufficiently stable to be applied to the treatment of blood vessels asdescribed in EP 0656203 and U.S. Pat. No. 5,676,962. Such foam isfurthermore incapable of being passed through a syringe needle withoutsignificant reversion to liquid and gas phases. It will be realised bythose skilled in the art that the microfoam technique exploits theability of the gas to deliver the sclerosant solution to the wall of thevessel to be treated, rather than to allow its dilution in blood as inthe liquid phase.

Aerosol units that are capable of producing foam have been described inthe prior art. U.S. Pat. No. 3,471,064 describes a device wherein air isdrawn into a foamable liquid through a series of small holes in the diptube of the unit. Such a device is not sterile in operation as it relieson its contents being open to the air. Foam so produced would appear tovary in properties dependent upon how much air is drawn in. A furtherdevice is described in U.S. Pat. No. 3,428,222 and utilises a wickingand foaming element in a compressible container that again draws in airto produce foam.

U.S. Pat. No. 3,970,219 describes sealed aerosol devices which arecapable of using pharmacologically inert gases to foam and expel liquidcompositions, It describes devices which produce foam by passage of thepropellant through a material having pores of 0.01 to 3 mm diameter froma lower propellant gas holding chamber to an upper foam holding chamber.The liquid to be foamed sits in the upper chamber or is absorbed ontothe porous material by shaking the container or is wicked up from alower chamber. This patent teaches that liquid from foam in the upperchamber drains down into the lower chamber, such that the thinnestwalled bubbles are expelled, and teaches that the propellant gas shouldbe ‘less soluble’, such as nitrogen, fluorocarbon or hydrocarbon, whereaqueous liquids are to be foamed.

Similar bubbler devices are used in accessories for use with‘environmentally friendly’ aerosol devices that operate using air underlow pressure, ie. hand pump conditions. Two such devices are supplied byAirspray International as the ‘Airspray® Finger Pump Foamer’ and‘Airspray Mini-Foamer’. The former is said to be suitable for simplewater based formulations while the latter is suggested for cosmetics,hair or skin care preparations. A second such device is provided as anoptional extra in the Swedspray/Eurospray® hand pump device as a foamingnozzle. This device is marketed as being suitable for use to ‘make youown cleansing foam or shaving lather’.

However, the present inventors have found that use of the availablehand-pump devices themselves, which in any case are not sterile, cannotproduce good microfoam with high loadings of carbon dioxide due tooutgassing, nor with inclusion of significant amounts of glycerol whichotherwise stabilises microfoam. Furthermore, when significantback-pressure is applied to the outlet of such device, such as whenattached to a syringe to be loaded for injecting the foam, stutteringoccurs. Use of low ejection velocity with this device can cause wettingat the nozzle which results in large bubbles caused by air entrapment.In any case the foams so produced, whether with oxygen or carbondioxide, tend to be very dry, with resultant need for high concentrationof sclerosant to be included, and tendency to break up on passage down aneedle.

It is preferred not to unnecessarily use high concentrations ofsclerosant in the solution as this could result in overdosage should adispensing device fail and deliver a more dense microfoam, ie. includinga higher proportion of liquid than intended.

Thus there is a need to provide a method and device that are capable ofproducing a uniform injectable microfoam made with a relatively lowconcentration of a sclerosing agent and a significant amount of a blooddispersible gas in sterile fashion without volatile liquid propellantsor the need for the operator to directly be concerned in control of itsparameters.

The present applicants have now provided a method and devices capable ofaddressing at least some of the aforesaid needs and have produced anovel stable injectable sclerosing microfoam with that method anddevices.

For the purpose of this application terms have the followingdefinitions: Physiologically acceptable blood dispersible gas is a gasthat is capable of being substantially completely dissolved in orabsorbed by blood. A sclerosant liquid is a liquid that is capable ofsclerosing blood vessels when injected into the vessel lumen.Scleropathy or scelrotherapy relates to the treatment of blood vesselsto eliminate them. An aerosol is a dispersion of liquid in gas. A majorproportion of a gas is over 50% volume/volume. A minor proportion of agas is under 50% volume/volume A minor amount of one liquid in anotherliquid is under 50% of the total volume. Atmospheric pressure and barare 1000 mbar gauge. Half-life of a microfoam is the time taken for halfthe liquid in the microfoam to revert to unfoamed liquid phase.

In a first aspect of the present invention there is provided a methodfor producing a microfoam suitable for use in scleropathy of bloodvessels, particularly veins, characterised in that it comprises passinga mixture of a physiologically acceptable blood dispersible gas and anaqueous sclerosant liquid through one or more passages having at leastone cross-sectional dimension of from 0.1 to 30 μm, the ratio of gas toliquid being controlled such that a microfoam is produced having adensity of between 0.07 g/ml to 0.19 g/ml and a half-life of at least 2minutes.

Preferably the microfoam is such that 50% or more by number of its gasbubbles of 25 μm diameter and over are no more than 200 μm diameter.

Preferably the gas/liquid ratio in the mix is controlled such that thedensity of the microfoam is 0.09 g/ml to 0.16 g/ml, more preferably 0.11g/ml to 0.14 g/ml.

Preferably the microfoam has a half-life of at least 2.5 minutes, morepreferably at least 3 minutes. The half-life may be as high as 1 or 2hours or more, but is preferably less than 60 minutes, more preferablyless than 15 minutes and most preferably less than 10 minutes.

Half-life is conveniently measured by filling vessel with a known volumeand weight of foam and allowing liquid from this to drain into agraduated vessel, the amount drained in a given time allowingcalculation of half-life ie. of conversion of microfoam back into itscomponent liquid and gas phases. This is preferably carried out atstandard temperature and pressure, but in practice ambient clinic orlaboratory conditions will suffice.

Advantageously and preferably the method provides a foam characterisedin that at least 50% by number of its gas bubbles of 25 μm diameter andover are of no more than 150 μm diameter, more preferably at least 95%of these gas bubbles by number are of no more than 280 μm diameter.Still more preferably at least 50% by number of these gas bubbles are ofno more than 130 μm diameter and still more preferably at least 95% ofthese gas bubbles by number are of no more than 250 μm diameter.

Preferably the mixture of gas and sclerosant liquid is in the form of anaerosol, a dispersion of bubbles in liquid or a macrofoam. By macrofoamis meant a foam that has gas bubbles that are measured in millimetreslargest dimension, eg. approximately 1 mm and over, and over such as canbe produced by lightly agitating the two phases by shaking. Preferablythe gas and liquid are in provided in the form of an aerosol where asource of pressurised gas and a means for mixing the two is provided tothe point of use. It may be preferred that a macrofoam is first producedwhere the liquid and gas are brought together only at the point of use.

The ratio of gas to liquid used in the mixture is important in order tocontrol the structure of the microfoam produced such that its stabilityis optimised for the procedure and the circumstances in which it isbeing carried out. For optimum foams it is preferred to mix 1 gramsclerosant liquid with from approximately 6.25 to 14.3 volumes (STP),more preferably 7 to 12 volumes (STP), of gas.

Preferably the physiologically acceptable blood dispersible gascomprises a major proportion of carbon dioxide and/or oxygen.Conveniently it may comprise a minor proportion of nitrogen or otherphysiologically acceptable gas. While a proportion of nitrogen may bepresent, as in air, the present invention provides for use of carbondioxide and/or oxygen without presence of nitrogen.

In one preferred form the gas used is a mixture of carbon dioxide andother physiological gases, particularly containing 3% or more carbondioxide, more preferably from 10 to 90% carbon dioxide, most preferably30 to 50% carbon dioxide. The other components of this gas arepreferably oxygen with a minor proportion only of nitrogen beingpreferred. Most preferably the other component is oxygen.

A further preferred form of gas comprises 50% vol/vol or more oxygen,the remainder being carbon dioxide, or carbon dioxide, nitrogen andtrace gases in the proportion found in atmospheric air. One preferredgas is 60 to 90% vol/vol oxygen and 40 to 10% vol/vol carbon dioxide,more preferably 70 to 80% vol/vol oxygen and 30 to 20% vol/vol carbondioxide. More preferred is 99% or more oxygen.

It is found that passing a stream of the sclerosant liquid and the gasunder pressure through one or more passages of 0.1 μm to 30 μm asdescribed provides a stable blood dispersible gas based sclerosantinjectable microfoam that was previously though to be only producible bysupply of high amounts of energy using high speed brushes and blenders.

Preferably the sclerosing agent is a solution of polidocanol or sodiumtetradecylsulphate in an aqueous carrier, eg water, particularly in asaline. More preferably the solution is from 0.5 to 5% v/v polidocanol,preferably in sterile water or a physiologically acceptable saline, eg.in 0.5 to 1.5% v/v saline. Concentration of sclerosant in the solutionwill be advantageously increased for certain abnormalities such asKlippel-Trenaunay syndrome.

Polidocanol is a mixture of monolaurylethers of macrogols of formulaC₁₂C₂₅(OCH₂CH₂)_(n)OH with an average value of n of 9. It will berealised that mixtures with other alkyl chains, oxyalkyl repeat unitsand/or average values of n might also be used, eg. 7 to 11, but that 9is most conveniently obtainable, eg. from Kreussler, Germany, eg asAethoxysklerol.

Most preferably the concentration of sclerosant in the aqueous liquid isa 1-3% vol/vol solution, preferably of polidocanol, in water or saline,more preferably about 2% vol/vol. The water or saline also, in somecases at least, preferably contain 2-4% vol/vol physiologicallyacceptable alcohol, eg ethanol. Preferred saline is buffered. Preferredbuffered saline is phosphate buffered saline. The pH of the buffer ispreferably adjusted to be physiological, eg from pH6.0 to pH8.0, morepreferably about pH7.0.

The sclerosant may also contain additional components, such asstabilising agents, eg foam stabilising agents, eg such as glycerol.Further components may include alcohols such as ethanol.

The aerosol, dispersion or macrofoam is preferably produced by mixingthe gas and liquid from respective flows under pressure. The mixingconveniently is carried out in a gas liquid interface element such asmay be found in aerosol canisters. The interface device may however bevery simple, such as a single chamber or passage of millimetredimensions, ie. from 0.5 to 20 mm diameter, preferably 1 to 15 mmdiameter, into which separate inlets allow entry of gas and liquid.Conveniently the interface is of design which is commonly found inaerosol canisters but which is selected to allow the correct ratio ofgas to liquid to allow formation of a foam of the presently defineddensity. Suitable inserts are available from Precision Valves(Peterborough UK) under the name Ecosol and are selected to produce theratio specified by the method above.

However, the mixing of gas and liquid may also be brought about within adip-tube leading from the sclerosant solution located in the bottom of apressurised container where holes in the dip-tube allow gas to enterinto a liquid stream entering from the bottom of the tube. In this casethe holes may be of similar diameter to the Ecosol holes. Such holes maybe conveniently produced by laser drilling of the dip-tube.

The one or more passages through which the aerosol or macrofoam soproduced arc passed to produce the stable microfoam preferably havediameter of from 5 μm to 25 μm, more preferably from 10 μm to 20 μmwhere simple passages arc provided, such as provided by openings in amesh or screen, eg. of metal or plastics, placed perpendicular to theflow of gas/liquid mixture. The passage is conveniently of circular oreliptical cross section, but is not necessarily so limited. A number ofsuch meshes or screens may be employed along the direction of flow.

Most preferably the passages are provided as multiple openings in one ormore elements placed across the flow. Preferably the elements are from 2to 30 mm diameter, more preferably 6 to 15 mm diameter, face on to theflow, with 5 to 65% open area, eg 2% to 20% open area for woven meshesand 20% to 70% open area for microporous membranes. Openings in a porousmaterial, such as provided in a perforated body, preferably provideseveral hundreds or more of such passages, more preferably tens orhundred of thousands of such passages, eg. 10,000 to 500,000, presentedto the gas liquid mixture as it flows. Such material may be a perforatedsheet or membrane, a mesh, screen or sinter. Still more preferably anumber of sets of porous material are provided arranged sequentiallysuch that the gas and liquid pass through the passages of each set. Thisleads to production of a more uniform foam.

Where several elements are used in series these are preferably spaced 1to 5 mm apart, more preferably 2 to 4 mm apart eg. 3 to 3.5 mm apart.

For some embodiments of the present invention it is found that thepassage may take the form of a gap between fibres in a fibrous sheetplaced across the path of the gas/liquid flow, and the dimensiondescribed in not necessarily the largest diameter, but is the width ofthe gap through which the gas/liquid aerosol or macrofoam must flow.

Alternatively the method provides for passing the mixture of gas andliquid through the same set of passages, eg as provided by one or moresuch porous bodies, a number of times, eg. from 2 to 2,000, morepreferably 4 to 200 times, or as many times as conveniently results in amicrofoam of the required density set out above. It will be realisedthat the more times the microfoam passes through the meshes, the moreuniform it becomes.

The pressure of the gas used as it is passed through the passages willdepend upon the nature of the mechanism used to produce the foam. Wherethe gas is contained in a pressurised chamber, such as in an aerosolcanister, in contact with the liquid, suitable pressures are typicallyin the range 0.01 to 9 bar over atmosphere. For use of meshes, eg 1 to 8meshes arranged in series, having apertures of 10-20 μm diameter, 0.1 to5 atmospheres over bar will, inter alia, be suitable. For use of 3-5meshes of 20 μm aperture it is found that 1.5-1.7 bar over atmosphericis sufficient to produce a good foam. For a 0.1 m pore size membrane, apressure of 5 bar or more over atmospheric pressure is preferred.

In one preferred form of the invention the passages are in the form of amembrane, eg of polymer such as polytetrafluoroeythylene, wherein themembrane is formed of randomly connected fibres and has a ratedeffective pore size which may be many times smaller than its apparentpore size. A particularly suitable form of this is a biaxilally orientedPTFE film provided by Tetratec™ USA under the trademark Tetratex®,standard ratings being 0.1 to 10 μm porosity. Preferred pore sizes forthe present method and devices are 3 to 7 μm. This material may belaminated with a porous backing material to give it strength and has theadvantage that one pass through may be sufficient to produce a foam thatmeets the use requirements set out above with regard to stability.However, it will evident to those skilled in the art that use of morethan one such membrane in series will give a still more uniform foam forgiven set of conditions.

It is believed that the combination of provision of a stream of solutionand gas under pressure through an aerosol valve and then flow throughthe passages, eg. pores in a mesh, screen, membrane or sinter providesenergy sufficient to produce a stable aqueous liquid soluble gas, egcarbon dioxide and/or oxygen, based sclerosant microfoam that waspreviously though to be only producible by supply of high amounts ofenergy using high speed brushes and blenders as described in the priorart.

Preferably the method of the invention provides a microfoam having atleast 50% by number of its gas bubbles of 25 μm diameter or over beingno more than 120 μm diameter. Preferably at least 95% of its gas bubblesof 25 μm diameter or over are of no more than 250 μm diameter. Diameterof such bubbles may be determined by the method set out in the Example 6set out herein.

A most preferred method of the invention provides a housing in which issituated a pressurisable chamber. For sterile supply purposes this willat least partly filled with a sterile and pyrogen free solution of thesclerosing agent in a physiologically acceptable aqueous solvent butotherwise may be charged with such at the point of use. This convenientmethod provides a pathway by which the solution may pass from thepressurisable chamber to exterior of the housing through an outlet andmore preferably a mechanism by which the pathway from the chamber to theexterior can be opened or closed such that, when the container ispressurised, fluid will be forced along the pathway and through one ormore outlet orifices.

The method is particularly characterised in that the housingincorporates one or more of (a) a pressurised source of thephysiologically acceptable gas that is readily dispersible in blood, and(b) an inlet for the admission of a source of said gas; the gas beingcontacted with the solution on activation of the mechanism.

The gas and solution are caused to pass along the pathway to theexterior of the housing through the one or more, preferably multiple,passages of defined dimension above, through which the solution and gasmust pass to reach the exterior, whereby on contact with, eg flowthrough, the passages the solution and gas form a the microfoam.

Preferably the gas and liquid pass through a gas liquid interfacemechanism, typically being a junction between a passage and one or moreadjoining passages, and are converted to an aerosol, dispersion ofbubbles or macrofoam before passing through the passages, but asexplained they may be converted first to a macrofoam, eg. by shaking ofthe device, eg, by hand, or mechanical shaking device.

In a second aspect of the present invention there is provided a devicefor producing a microfoam suitable for use in scleropathy of bloodvessels, particularly veins, comprising a housing in which is situated apressurisable chamber containing a solution of the sclerosing agent in aphysiologically acceptable solvent referred to in the first aspect; apathway with one or more outlet orifices by which the solution may passfrom the pressurisable chamber to exterior of the device through saidone or more outlet orifices and a mechanism by which the pathway fromthe chamber to the exterior can be opened or closed such that, when thecontainer is pressurised and the pathway is open, fluid will be forcedalong the pathway and through the one or more outlet orifices

said housing incorporating one or more of (a) a pressurised source ofphysiologically acceptable gas that is dispersible in blood and (b) aninlet for the admission of said gas; the gas being in contacted with thesolution on activation of the mechanism such as to produce a gassolution mixture

said pathway to the exterior of the housing including one or moreelements defining one or more passages of cross sectional dimension,preferably diameter, 0.1 μm to 30 μm, through which the solution and gasmixture is passed to reach the exterior of the device, said passing ofsaid mixture through the passages forming a microfoam of from 0.07 to0.19 g/ml density and of half-life at least 2 minutes.

Preferably the microfoam has 50% or more by number of its gas bubbles of25 μm diameter and over of no more than 200 μm diameter.

More preferably the microfoam is from 0.09 to 0.16 g/ml density and mostpreferably of 0.11 μg/ml to 0.14 g/ml.

Preferably the microfoam has a half-life of at least 2.5 minutes, morepreferably at least 3 minutes.

Advantageously and preferably this device provides a microfoamcharacterised in that at least 50% by number of its gas bubbles of 25 μmdiameter and over are of no more than 150 μm diameter or less, morepreferably at least 95% by number of these gas bubbles are of diameter280 μm or less. Still more preferably at least 50% by number of thesegas bubbles are of no more than 120 μm diameter and still morepreferably at least 95% of these gas bubbles are of no more than 250 μmdiameter.

Preferably the apparatus includes a chamber, eg such as in a sealedcanister, charged with the blood dispersible gas and the sclerosantliquid, eg. in a single chamber, the device pathway including a dip tubewith an inlet opening under the level of the liquid in this chamber whenthe device is positioned upright. Preferably the dip-tube has an outletopening at a gas liquid interface junction where the gas, which residesin the chamber above the liquid, has access to the pathway to the deviceoutlet. The pathway is opened or closed by a valve element which isdepressed or tilted to open up a pathway to the exterior of the device,whereby the liquid rises up the dip tube under gas pressure and is mixedin the interface junction with that gas to produce an aerosol,dispersion of bubbles in liquid or macrofoam.

Either inside the pressurisable chamber disposed in the pathway to thevalve, or on the downstream side of the valve, is provided an elementhaving the one or more passages described in the first aspect mountedsuch that the gas liquid mixture, ie. dispersion of bubbles in liquid,aerosol or macrofoam, passes through the passage or passages and iscaused to foam. This element may conveniently be located in a cap on thecanister in between the valve mounting and an outlet nozzle.Conveniently depression of the cap operates the valve. Alternatively theelement is within the canister mounted above the gas liquid interface.

In an alternate embodiment of this device the gas liquid interface maycomprise holes in the dip tube above the level of the liquid in thecanister inner chamber.

The gas pressure employed will be dependent upon materials being usedand their configuration, but conveniently will be 0.01 to 9 bar overatmospheric, more preferably 0.1-3 bar over atmospheric, and still morepreferably 1.5-1.7 bar over atmospheric pressure.

A preferred device of this aspect of the invention is of the‘bag-on-valve’ type. Such device includes a flexible gas and liquidtight container, forming a second inner chamber within the pressurisablechamber, which is sealed around the dip-tube and filled with the liquid.More preferably the dip-tube has a one-way valve located at a positionbetween its end located in the sclerosant liquid and the gas liquidinterface junction, which when the passage to the exterior is closed,remains closed such as to separate the liquid from the physiologicallyacceptable blood dispersible gas around it in the chamber. On openingthe pathway to the exterior, the one way valve also opens and releasesliquid up the dip-tube to the gas liquid interface where an aerosol isproduced which is in turn then passed through the passages to beconverted to microfoam. A suitable one-way valve is a duck-bill typevalve, eg such as available from Vernay Labs Inc, Yellow Springs, Ohio,USA. Suitable bag-on-valve can constructions are available from CosterAerosols, Stevenage, UK and comprise an aluminium foil/plasticslaminate.

Conveniently the one way valve is located at the top of the dip-tubebetween that and the gas liquid interface junction, ie. an Ecosoldevice. This allows filling of the bag before application of the one wayvalve, followed by sterilisation of the contents, whether in thecanister or otherwise.

Such a preferred device has several potential advantages. Where oxygenis the gas, this is kept separate from the liquid before use and thusreduces possibility of oxygen radicals reacting with organic componentsin the liquid, eg. during sterilisation processes such as irradiation.Where carbon dioxide is the gas, storage can lead to high volumes of gasdissolving in the liquid, which on release to the atmosphere or lowerpressure, could out-gas and start to destroy the microfoam too quickly.Such separation also prevents the deposition of solidified sclerosingagent components in the dimension sensitive orifices of the device in anunused can in storage or transit, particularly should that be orientedother than upright.

It is preferred that the gas liquid interface is provided as a definedorifice size device such as the Ecosol device provided by PrecisionValve Peterborough UK. For a device where the passages of defineddimension are outside of the pressurised chamber, ie. mounted on thevalve stem, the ratio of area of the gas holes to the liquid holesshould be of the order of 3 to 5, preferably about 4. Where the passagesare inside the pressurised chamber this is preferably higher.

A third aspect of the invention provides a device for producing amicrofoam suitable for use in sclerotherapy of blood vessels,particularly veins, comprising a housing in which is situated apressurisable chamber, at least part filled or fillable with a solutionof a sclerosing agent in a physiologically acceptable solvent and/or aphysiologically acceptable blood dispersible gas; a pathway by which thecontents of the chamber may be passed to exterior of the housing throughone or more outlet orifices and a mechanism by which the chamber can bepressurised such that its contents pass to the exterior along thepathway and through one or more outlet orifices

said pathway to the exterior of the housing or the chamber including oneor more elements defining one or more passages of cross sectionaldimension, preferably diameter, 0.1 μm to 30 μm through which thecontents of the chamber may be passed, whereby on passing through thepassages the solution and gas form a microfoam of from 0.07 to 0.19 g/mldensity and having a half-life of at least 2 minutes.

Preferably the microfoam is such that 50% or more by number of its gasbubbles of 25 μm or more diameter are of no more than 200 μm diameter.

Preferably the microfoam is of density 0.09 to 0.16 g/ml and morepreferably of 0.1 g/ml to 0.14 g/ml. The preferred limits on bubble sizeare also as for the first and second aspects.

Preferably the microfoam has a half-life of at least 2.5 minutes, morepreferably at least 3 minutes

The elements defining the passages in the pathway or chamber may bestatic or may be moveable by manipulation of the device from outside ofits interior chamber.

Such device may be conveniently constructed in the form of a syringedevice, comprising a syringe barrel and a functionally co-operatingsyringe plunger defining a chamber, the plunger being the means forpressurising the chamber, that chamber containing the gas and liquid inuse, but which is particularly characterised by being formed with thepassages of aforesaid dimension adjacent or at the needle affixing endof the syringe body, eg at a luer connection opening.

In use such a device is partially charged with the required sclerosantliquid and then charged with the physiologically acceptable gas, or viceversa, by withdrawing the syringe plunger while connecting the lueropening to a source of each in turn. Alternatively these may be mixedbeforehand as a macrofoam, or even as a microfoam which by its naturewill be breaking down. Where the gas and liquid are charged as separatephases the syringe contents may be agitated such as to produce a foam.The plunger is then pushed into the syringe body whereby this foampasses through the passages and is converted to a microfoam having therequired stability for the procedure concerned. Where the gas and liquidare charged together as a foam, operation of the plunger will providethe microfoam.

In a preferred embodiment of this device two chambers are provided andare linked to each other through a passage, eg including the syringebody luer connector orifice, via the one or more passages of 0.1 μm-30μm dimension. In this manner reciprocation of a plunger in one or bothof the chambers results in the gas and liquid being passed through thepassages of defined dimension a desired number of times to produce thedesired foam.

In an alternative embodiment an element defining a number of thepassages of said dimension is provided within the chamber such that itcan be moved in either direction to pass chamber contents through itspassages. Conveniently this element may be mounted on a support, such asa support plunger rod coaxial to the syringe plunger rod. The elementmay incorporate any of the porous passageway defining items referred toabove, but conveniently includes meshes or a porous membrane mountedwith major surfaces perpendicular to the syringe barrel/chamberlongitudinal axis such that movement of the support rod in eitherdirection longitudinally results in a sweeping action by the elementsuch that chamber contents, gas and liquid, are passed through thepassages together. It will be realised that once such a device ischarged with a suitable ratio of gas and liquid, it may also be shakento give a loose macrofoam as a first step.

Preferably the housing is a container defining a chamber in which issituated the solution and gas under pressure and the pathway is aconduit leading from the chamber in the interior of the container to avalve closing an opening in the container wall.

Preferred forms of the one or more elements defining the multiplepassages for use in the device of the present invention are meshes,screens or sinters. Thus one or more meshes or perforated screens orsinters will be provided, with some preferred forms employing a seriesof such elements arranged in parallel with their major surfacesperpendicular to the path of solution/gas expulsion.

It is preferred that all elements of any of the devices according to theinvention having a critical dimension are made of a material that doesnot change dimension when exposed to aqueous material. Thus elementswith such function such as the air liquid interface and the elementdefining the passages of 0.1 μm-30 μm dimension preferably should not beof a water swellable material such as Nylon 66 where they are likely tobe exposed to the solution for more than a few minutes. Where suchexposure is likely these parts are more preferably being fashioned froma polyolefin such as polypropylene or polyethylene.

Preferably the canister or syringe device is sized such that it containssufficient gas and solution to form up to 500 ml of microfoam, morepreferably from 1 ml up to 200 ml and most preferably from 10 to 60 mlof microfoam. Particularly the amount of gas under pressure in suchcanisters should be sufficient to produce enough foam to treat, ie.fill, at least one varicosed human saphenous vein. Thus preferredcanisters of the invention may be smaller than those currently used forsupply of domestic used mousse type foams. The most preferred canisterdevice is disposable after use, or cannot be reused once opened such asto avoid problems of maintaining sterility.

It may be preferred to incorporate a device which maintains gas pressurein the canister as foam is expelled. Suitable devices are such asdescribed under trademarked devices PECAP and Atmosol. However, where asignificant headspace or pressure of gas is provided this will not benecessary.

In order to ensure that the microfoam delivered from devices of theinvention is not ‘outside’ specification, ie. falls within the desireddensity, bubble size and half life parameters set out above, the presentinvention provides a further, fourth, aspect which provides a devicewhich is positioned to receive microfoam emitted from the device of thesecond and third aspects of the invention, which device allows ventingof the first portion of microfoam to waste and passage of a secondportion of microfoam to a delivery device, such as a syringe, in sterilefashion.

A device of the fourth aspect comprises an inlet conduit being adaptedto engage the outlet of a microfoam producing device of the second orthird aspect in a microfoam tight fashion, the conduit being connectedto and leading through a multipath tap capable of being set to directmicrofoam passing down the conduit to one or both of first and secondcontiguous outlet conduits or to close the inlet conduit, at least oneof the first and second outlet conduits being adapted to receive theluer connector of a syringe. Preferably the device also comprises one ormore elements for engaging the device of the second or third aspectother than by its outlet nozzle to hold it securely, eg upright in thecase of a canister with a dip-tube.

Preferably the device of the fourth aspect comprises a three-way tap.More preferably the device of the fourth aspect comprises a baseelement, sufficiently stable to mount a microfoam producing device ofthe second or third aspects when engaged thereby. Preferably themicrofoam producing device is engaged by resilient elements which locateit securely adjacent the three-way tap whereby the inlet conduit can beattached to the microfoam producing device outlet conduit.

Particularly preferred the device of the fourth aspect comprises a baseelement adapted mount the microfoam dispensing device and an activatingelement which operates to cause the pathway to be opened the to theinlet conduit. In this manner when the multi-way tap is shut, thedispensing device contents remain therein, but when the multi-way tap isopened to either of its outlet conduits it immediately causes release offoam generated by the device.

A further aspect of the present invention provides improved microfoamsfor use in the elimination of blood vessels and vascular malformationsthat are made available by the method and devices of the inventioncharacterised in that they comprise a physiologically acceptable gasthat is readily dispersible in blood together with an aqueous sclerosantliquid characterised in that the microfoam has a density of from 0.07 to0.19 g/cm and is capable of being passed down a 21 gauge needle withoutreverting back to gas and liquid by more than 10%, based on liquidcontent reverting back to unfoamed liquid phase.

Preferably the microfoam, on passage through said needle, does notrevert back to unfoamed liquid by more than 5% based on liquid content,still more preferably by no more than 2%.

Preferably the microfoam is capable of being passed down a needle whileretaining at least 50% by number of its gas bubbles of at least 25 μmdiameter at no more than 200 μm diameter. This is conveniently measuredunder ambient conditions, more preferably at STP.

Preferably at least 50% by number of said gas bubbles remain at no morethan 150 μm diameter and at least 95% of these bubbles at no more than280 μm diameter. Preferably the microfoam has a half-life as measured bydrainage through a funnel of 2 cm neck diameter and drainage path 10 cmof at least 2 minutes, more preferably 2.5 minutes and most preferably 3minutes. This may be carried out at ambient temperature or STP. Mostconveniently the funnel is pre-equilibrated in a water bath to ensure atemperature of 25° C. before drying and application of foam. Placing ofa microfoam filled syringe upside down, without its plunger, above thefunnel leading into a graduated receptacle allows convenient measurementof this parameter.

Preferably the gas includes less than 40% v/v nitrogen. Preferably thedensity of the microfoam is from 0.09 to 0.16 g/ml, more preferably 0.1g/ml to 0.14 g/ml.

Advantageously and preferably at least 50% by number of the gas bubblesof 25 μm diameter or more are of no more than 120 μm diameter and stillmore preferably at least 95% of these gas bubbles are of diameter 250 μmor less.

Preferably the foam density, which is a measure of liquid/gas ratio, isfrom 0.13 to 0.14 g/cm and the half-life is at least 2.5 minutes. Thefoam more preferably does not move outside of its parameters of bubblesize set out above in such time.

Preferably the gas consists of at least 50% oxygen or carbon dioxide,more preferably 75% or more oxygen or carbon dioxide and most preferablyat least 99% oxygen or carbon dioxide, eg substantially 100% oxygen orcarbon dioxide. Preferably the oxygen or carbon dioxide is medicalgrade.

Preferably the sclerosant is aqueous polidocanol or sodium tetradecylsulphate.

When the sclerosant is aqueous polidocanol the concentration ofpolidocanol is from 0.5 to 4% vol/vol in the liquid, preferably being 1to 3% vol/vol polidocanol and most preferably being 2% vol/vol in theliquid.

Advantageously the sclerosant is made up in water, but moreadvantageously is made up in a saline solution, particularly 10 to 70 mMphosphate buffered saline, eg. 50 mM phosphate buffered saline, andpreferably of pH6 to pH8.0 eg. about pH 7.0. Advantageously the aqueoussolution contains a minor amount of an alcohol, preferably 96% ethanol,eg at between 2 and 6% vol/vol, more preferably at about 4% vol/vol of96% ethanol.

Addition of glycerol to the aforesaid sclerosant imparts a longerhalf-life to the resultant foam. However, glycerol also produces atendency for the meshes to block up when using a mesh device asdescribed above, so should be used carefully where the device it isproduced from may be used multiple times or the bag-on-valve concept isused.

The present invention will now be described further by way ofillustration only by reference to the following Figures and Examples.Further embodiments falling within the scope of the invention will occurto those skilled in the art in the light of these.

FIGURES

FIG. 1: Shows a cross-sectional view of a canister device of the secondaspect of the invention as further described in Example 2 below.

FIG. 2: Shows a cross-sectional view of a canister device of the secondaspect incorporating a bag-on-valve reservoir for the sclerosant withthe gas being in the outer chamber and separated therefrom by a one wayduck-bill valve.

FIG. 3: Shows a cross-sectional view of a syringe-like device of thethird aspect incorporating a set of meshes across its dispensingchamber.

FIG. 4: Shows a cross-sectional view of a syringe-like device of thethird aspect incorporating a porous membrane supported on an innerplunger rod such that it can be reciprocated within the syringe chambercontents.

FIG. 5: Is a bar chart and graph illustrating distribution of gas bubblediameter in a preferred 0.13 g/ml oxygen/air/polidocanol microfoam ofthe fourth aspect.

FIG. 6: Is a bar chart and graph illustrating distribution of gas bubblediameter in microfoams of 0.09 g/ml and 0.16 g/ml of the fourth aspect.

FIG. 7: Is a graph showing the effect of passing a preferred foam of thefourth aspect down a 21 gauge needle as compared to control fresh andsimilarly aged microfoams.

FIG. 8: Is a graph showing the effect of passing a 2% vol polidocanolsolution dry microfoam of 0.045 g/ml, such as producible by use of aprior art bubbler device (Swedspray valve, Ecosol insert and head), downa 21 gauge needle.

FIG. 9: Is a graph showing the effect of passing a 1% vol polidocanoldry microfoam of 0.045 g/ml such as producible by use of the prior artbubbler device (Swedspray valve, Ecosol insert and head), down a 21gauge needle.

FIG. 10: is an elevation view of a syringe filling device of the fourthaspect.

FIG. 11: Is a plan view of the device of FIG. 10.

EXAMPLES Example 1

A standard aerosol canister with a one way depressible action valve ischarged half full with a 3% v/v solution of polidocanol in sterile waterand pressurised to 3 atmospheres with a 50:50 mix of carbon dioxide andoxygen. On the valve stem is mounted an actuator and delivery head whichcarries four plastics screens, just under 0.5 mm thick, perforated with20 μm diameter passages, these screens being of the general typeprovided in the Swedspray-Eurospray foaming actuator cap ApRisC® device.The valve is fed through an Ecosol gas liquid interface insert from adip-tube and the surrounding chamber. Gas inlet sizes (×2) into theinsert are 0.006″×0.01″ while the single liquid inlet is 0.024″, ascontrolled by selecting Ecosol insert size. On depression of the headthe aerosol valve releases pre-mixed solution and gas onto the screenswhereupon a microfoam suitable for scleropathy and that is dimensionallystable for at least 2 minutes, preferably 5 minutes using glycerol inthe is produced.

Example 2

FIG. 1 illustrates a further canister design of the invention whereinthe passages through which the gas liquid mixture must travel are placedwithin the pressurised chamber, thus increasing hygiene of the device.

The canister is of standard 500 ml design with an aluminium wall (1),the inside surface of which is coated with an epoxy resin resistant toaction of polidocanol and oxygen (eg Hoba 7940-Holden UK)). The bottomof the canister (2) is domed inward. The canister inner chamber (4) ispre-purged with 100% oxygen for 1 minute, containing 15 ml of a 2%vol/vol polidocanol/20 mmol phosphate buffered saline solution (3) thenfilled with the oxygen at 2.7 bar gauge (1.7 bar over atmospheric). Thisis provided by overpressuring the polidocanol part filled can with 1.7bar oxygen.

The dome provides a perimeter area around the bottom of the innerchamber in which a level of polidocanol solution is retained sufficientfor the bottom open end of a dip tube to be submerged therein when thetop of the dome is no longer covered with the solution. In this manner,by use of an indicia on the outside of the canister to indicate theposition of the dip tube, the canister can be oriented to extract thelast fraction of solution if desired. In practice a vertical orientationis sufficient.

A standard 1″ diameter aerosol valve (5) (Precision Valves,Peterborough) is crimped into the top of the canister after sterile partfilling with the solution and is activatable by depressing an actuatorcap (6) to release content via an outlet nozzle (13) sized to engage aluer fitting of a syringe or multi-way connector (not shown). A furtherconnector (7) locates on the bottom of the standard valve and mounts,preferably by interference fit, four Nylon 66 meshes held in highdensity polyethylene (HDPE) rings (8) all within an open endedpolypropylene casing. These meshes have diameter of 8 mm and have a 15%open area made up of 20 μm pores, with the meshes spaced 3.5 mm apart bythe HDPE rings.

A further connector (9) locates on the bottom of the connector holdingthe meshes and receives a housing (10) which mounts the dip tube (12)and includes gas receiving holes (11 a, 11 b) which admit gas fromchamber (4) into the flow of liquid which rises up the diptube onoperation of the actuator (6). These are conveniently defined by anEcosol device with insert as before. Holes (11 a,11 b) havecross-sectional area such that the sum total ratio of this to thecross-sectional area of the diptube is controlled to provide therequired gas/liquid ratio. This is for example 0.010″×0.013″ each hole(11 a, 11 b) to 0.040″ liquid receiving hole.

Example 3

A further canister embodiment of the present invention is shown in FIG.2, which is broadly as shown in FIG. 1, but for the inclusion of amodified ‘bag-on-valve’arrangement. In this embodiment the polidocanolsclerosing solution (3) is enclosed in a foil bag (22), comprising analuminium foil/plastics laminate (Coster Aerosols Stevenage UK) sealedin gas tight fashion to dip-tube (12). At the top end of the dip-tube isa one-way duck-bill valve (Vemay Labs Inc Ohio USA) that serves toprevent contact of polidocanol with the contents of the dip-tube (12)and chamber (4) until the valve (5) is operated. On said operation thevalve (21) opens and polidocanol solution (3) is caused to rise up thedip-tube (12), whereby it becomes mixed with the air/oxygen gas mixtureentering through holes (11 a, 11 b). In this manner the can may besafely sterilised with ionising radiatons which may otherwise causeinteractions between radical species in the gas and the organiccomponent of the polidocanol solution. Such arrangement can also improvethe operation of the canister with regard to start up of foam delivery.The bag (22) preferably substantially only contains the liquid (3), withno head-space gas above it.

Example 4

The device of this example is identical with that of Example 3, savethat the polidocanol in the liquid is replaced with a sodiumtetradecylsulphate at 1% vol/vol, all other ingredients being the same.

Example 5

FIG. 3 shows a syringe device that is specifically designed to producemicrofoam according to the invention using the method of the invention.Syringe body (13) has a luer opening (14) and locating flanges (15) andcooperates with a plunger (16) to define a chamber (19). Chamber (19) isprefilled, or filled in use, with sclerosing solution (18), in this casepolidocanol as above. The plunger has a sealing face (17) that is inertwith respect to the polidocanol solution and which ensures that saidsolution does not escape around the sides of the plunger when that isdepressed to pressurise the contents of chamber (19).

Located between the plunger sealing face (17) and luer opening (14) is aseries of three spaced meshes (20) of the type and configurationreferred to in Example 2. In this example the meshes are located such asto leave a space between them and the luer opening such that a physiciancan see the foam produced by passage of gas/liquid mixture through themeshes.

In operation such a syringe is preferably provided with the plungerpushed in such as to define a reduced chamber (19) volume filled withsclerosing solution with the luer opening sealed in a sterile fashion,eg. by a foil seal cap attached to its exterior. The cap is peeled off,the luer attached to a source of required blood dispersible gas and theplunger withdrawn to admit a required amount of gas to give a ratio ofgas to liquid suitable such that when agitated, eg. by shaking thesyringe, a macrofoam is produced containing a 7:1 to 12:1 ratio gas toliquid. For production of foam the plunger is depressed with an evenpressure, such as to depress at 1 ml/second, and the macrofoam isconverted to microfoam.

It will be realised that the microfoam could be directly applied to apatient, but more conveniently would be transferred directly to achamber, eg a second syringe, where viewing of a large volume of foamsuch as would be required to eliminate a large saphenous vein, would bemore readily performed. In this manner, should it be desired, themicrofoam could be passed between the two chambers via the meshes inorder to render it still more uniform in nature.

Example 6

FIG. 4 shows a further syringe device embodiment of the inventiondesigned to produce microfoam according to the invention using themethod of the invention. Syringe body (13) has a luer opening (14) andlocating flanges (15) and cooperates with a plunger (16) to define achamber (19). Chamber (19) is prefilled, or filled in use, withsclerosing solution (18), in this case polidocanol as above. The plungerhas a sealing face (17) that is inert with respect to the polidocanolsolution and which ensures that said solution does not escape around thesides of the plunger when that is depressed to pressurise the contentsof chamber (19).

Passing down the central longitudinal axis of the plunger is a rod (21)mounting a porous Tetratex membrane (22) of effective pore size about 5μm in a double ring mounting. The rod (21) has a handle (23) locatedoutside the syringe chamber which allows the membrane to be movedindependently of the plunger such as to force the contents of chamber(19) to pass through its pores.

In operation such a syringe is preferably provided with the plungerpushed in such as to define a reduced chamber (19) volume filled withsclerosing solution with the luer opening sealed in a sterile fashion,eg. by a foil seal cap attached to its exterior. The cap is peeled off,the luer attached to a source of required blood dispersible gas and theplunger withdrawn to admit a required amount of gas to give a ratio ofgas to liquid. Eg. a 7:1 to 12:1 ratio gas to liquid. For production offoam the handle (23) on rod (21) is operated to pass the membrane up anddown the chamber a number of times, eg 2 to 10 times, causing the gasand liquid to mix and produce foam. For dispensing of foam directly to apatient, or to another syringe or container, the rod (21) is withdrawnsuch that membrane mounting (22) abuts the plunger sealing face and theplunger is such depressed with an even pressure, eg. at 1 ml/second.Obviously when the foam is passed directly into a patient a suitableneedle is affixed to the luer connection.

Example 6

A microfoam of the invention is produced in a device as described inExample 1, having critical passage and gas mixing dimensions as set outin Example 2 but differing therefrom in that mesh is located in thedispensing cap, downstream of the valve, while gas/liquid mixing occursin an Precision Valves Ecosol insert device upstream of the valve. Thechamber (500 ml) is charged with 15 ml of an aqueous solution containingper 100 ml polidocanol (Kreussler-Germany) (2 ml), 96% ethanol (4 ml)and 55 mmol Phosphate Buffer (pH7.0) (94 ml) with gas being airoverpressured with 1.5 bar 100% oxygen. The characteristics of themicrofoam produced on operation of the valve are shown in FIGS. 5 and 6.FIG. 5 shows bubble size distribution immediately after microfoamgeneration; foam density being 0.138 g/ml. FIG. 6 shows bubble sizeproduced with varying ratio of gas to liquid, provided by altering thegas/liquid interface hole size (11 a, 11 b) to give foams of 0.09 g/ml(closed diamonds) and 0.16 g/ml (open circles). FIG. 7 shows the effecton bubble size distribution of a preferred microfoam (0.13 g/ml) afterpassage through a 21G needle: Open circles show fresh foam, crossescontrol foam aged to match injection time and closed diamonds show afterpassage through the needle. FIG. 8 shows the effect of passing amicrofoam made using a Swedspray device density 0.045 g/ml through theneedle. Closed diamonds are control aged while open circles are afterneedle passage.

Note, when 5% glycerol is added to the formulation, half life wasincreased to approximately 4 minutes.

Bubble sizes are calculated by taking up foam into a syringe through itsluer opening, optionally attaching a 21G needle, and injecting foambetween two glass slides that are separated using 23.25 micron diameterbeads (eg. available as microspheres from Park Labs USA).Maxtascan/Global Lab Image technique was used to analyse bubble size.Diameters of uncompressed bubbles (Dr) were calculated from diameters ofbubbles between slides (Df) using the equation Dr=3 √3Df²x/2 where x isthe distance between the slides. These measurements thus are made atambient temperature and pressure.

It will be realised that bubbles much smaller than 25 μm diameter may bepresent but not counted. The % figures given with respect to bubble thusrelate to bubbles in the range 25 μm and above.

Example 7

For filling of a syringe with microfoam of the invention the bottom of acanister of Example 1, 2 or 3 is placed into a receiving recess in thebase of a syringe filling device as shown in elevation in FIG. 10 andplan (FIG. 11). Canister (24) is inserted into a 1 cm deep recess (25)in a plastics base element (26), the recess being approximately 1 mm indiameter more than the canister such that a snug fit is provided. Thecanister is further supported by two resilient fixed arms (27 a, 27 b),fixed on vertical support rod (28) that deform to receive the canisterdiameter.

Just above the top of the position of the canister cap in use, thesupport rod (28) mounts an actuator arm that is lockable between a firstactuating position (full lines) an and an off position (dotted lines).In the actuating position the arm depresses the canister actuator cap(30), thus opening the canister valve and causing microfoam to bereleased.

Also on the base (26) is a recess (32) sized to snugly receive a syringe(34) with its plunger. A stop element (33) is provided that ispositioned such that on filling the plunger is limited in its range oflongitudinal movement such that the syringe cannot be overfilled.

A flexible transparent plastics tube (35), inert to the sclerosant foam,is attached to the canister outlet nozzle (31) in use and is fixed to athree way valve (36) affixed to the base (26). The valve is operated byturning a tap (37) to one of three positions: (a) valve shut-nomicrofoam passage (b) valve open to waste (38) whereby any microfoamthat by visual inspection of the contents of tube (35) appearsunsuitable, is vented and (c) valve open to syringe, whereby a setamount of microfoam passes through the syringe luer and fills it untilthe syringe plunger abuts the stop (33)

Example 8

20 mls microfoam of Example 6 is loaded into a 20 ml syringe using thedevice of Example 7 and the syringe disengaged from the device. A 19gauge needle is attached either directly to the syringe luer fitting orvia a catheter. The microfoam is administered into to a varicose veinwhile its advance and final position is monitored using a hand heldultrasound scanner such that the fresh foam is restricted in location tothe vein being treated. After between 1 and 5 minutes the vein contractsand subsequently becomes fibrosed.

1. A method for producing a microfoam suitable for use in sclerotherapyof blood vessels characterised in that it comprises passing a mixture ofa physiologically acceptable blood dispersible gas and an aqueoussclerosant liquid through one or more passages having at least onecross-sectional dimension of from 0.1 to 30 μm, the ratio of gas toliquid being controlled such that a microfoam is produced having adensity of between 0.07 g/ml to 0.19 g/ml and has a half-life of atleast 2 minutes. 2-67. (canceled)